The role of focal adhesions for immune cell migration in 3-dimensional environments

• Applicant: Professor Dr. Ben Fabry
• Subject Area: Biophysics
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 540981488

Immune cells such as neutrophils, macrophages, T-, B-, and NK-cells are known to migrate through a 3-D connective tissue matrix in a so-called amoeboid migration mode. Amoeboid migration is characterized by limited or no proteolytic activity, with limited or no specific adhesion to the extracellular matrix (ECM). Therefore, it is thought that these cells do not generate substantial traction forces, implying that they do not form focal adhesion contacts and therefore do not have the ability to significantly pull on and rearrange ECM fibers. Contrary to this prevailing theory, we recently discovered that immune cells can switch from their default amoeboid migration mode to a highly contractile, mesenchymal-like migration mode when they are confronted with high steric hindrance of the matrix, e.g.in the form of small pores. During brief contractile bursts lasting several minutes, the cells generate substantial traction forces of up to 100 nN, comparable to forces seen in mesenchymal cells such as fibroblasts or tumor cells after epithelial-mesenchymal transition. Such large traction forces are thought to require strong cell-matrix adhesions, for which integrins are the most likely candidates. By preventing strong integrin adhesion to the matrix or after blocking beta-1 and beta-2 integrins, we found that immune cells can still migrate amoeboidally with unchanged migration speed, but the cells are forced to take turns more frequently to evade small pores and obstacles (resulting in a reduced persistence), and they also get stuck more often (reduced motile fraction). In this project, we will explore how confinement and steric hindrance guide the regulation of integrin-mediated adhesions to the ECM for efficient immune cell migration.

• DFG Programme: Research Grants